The thiopurine base 6-mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are widely used in the treatment of chronic inflammatory diseases such as inflammatory bowel disease (IBD), haematological malignancies, and in transplantation. However, adverse drug reactions to AZA or 6-MP occur in 15% to 28% of patients (Schwab et al., Pharmacogenetics, 12:429-436 (2002); Lennard, Gut, 51:143-146 (2002); Sandborn et al., Cochrane Database Syst. Rev., CD000545 (2000); Ansari et al., Aliment. Pharmacol. Ther., 16:1743-1750 (2002)) and often necessitate withdrawal of therapy.
Genetic polymorphisms in the thiopurine methyltransferase gene (e.g., TPMT*2 to TPMT*8) are associated with deficient TPMT activity (Hon et al., Hum. Mol. Genet., 8:371-376 (1999); Spire-Vayron de la Moureyre et al., Hum. Mutat., 12:177-185 (1998); Otterness et al., J. Clin. Invest., 101:1036-1044 (1998); Otterness et al., Clin. Pharmacol. Ther., 62:60-73 (1997); Krynetski et al., Proc. Natl. Acad. Sci. USA, 92:949-953 (1995); Tai et al.,Am. J. Hum. Genet., 58:694-702 (1996)) and the level of TPMT activity has been shown to influence the therapeutic efficacy and toxicity of AZA and 6-MP (Lennard et al., Ther. Drug Monit., 18:328-334 (1996); Lennard et al., Clin. Pharmacol. Ther., 46:149-154 (1989); Lennard, Ther. Drug Monit., 20:527-531 (1998)). For example, a heterozygous TPMT genotype correlates with an increased risk of myelosuppression and other adverse drug reactions (Lennard, Gut, 51:143-146 (2002); Ansari et al., Aliment. Pharmacol. Ther., 16:1743-1750 (2002); Dubinsky et al., Gastroenterology, 118:705-713 (2000)). Further, patients with a complete TPMT deficiency are at high risk for severe myelosuppression induced by thiopurine therapy (Lennard et al., Arch. Dis. Child, 69:577-579 (1993); Lennard et al., Br. J. Clin. Pharnacol., 44:455-461 (1997); Relling et al., J. Natl. Cancer Inst., 91:2001-2008 (1999)). Consistent with the frequency of these alleles in Caucasian populations, adverse drug reactions in only 5 to 10% of patients treated with thiopurine drugs can be explained by the inheritance of one or two TPMT deficiency associated alleles. As a result, in the majority of patients, the pharmacogenetic basis of side-effects is unexplained.
Thus, there is a need to determine the pharmacogenetic basis of adverse drug reactions to AZA or 6-MP in the majority of patients by identifying additional polymorphisms in genes that can be used to predict a patient's tolerance to AZA or 6-MP. Further, there is a need to optimize therapy such as anti-inflammatory or immunosuppressive therapy by determining whether a patient should be given an alternative drug based on the presence or absence of genetic polymorphisms associated with a risk for adverse drug reactions. The present invention satisfies these and other needs.